tbuckley/cabot-search huggingface dataset:
PATH-46. A NOVEL POT1-TPD PRESENTATION: A GERMLINE POT1 MUTATION DISCOVERED IN A PATIENT WITH NEWLY DIAGNOSED POSTERIOR FOSSA EPENDYMOMA
Authors: Stephen Gilene, Scott Raskin, Somak Roy, Sara Knapke
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION POT1 tumor predisposition (POT1-TPD) is an autosomal dominant disorder characterized by increased lifetime malignancy risk. Melanoma, angiosarcoma and chronic lymphocytic leukemia are the most frequently reported malignancies. Other related cancers include gliomas. Protection of telomeres protein 1 is part of the shelterin protein complex to maintain/protect telomeres. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability. Ependymomas are a heterogeneous group comprising 12% of pediatric brain tumors and are locally aggressive with frequent recurrence. CASE PRESENTATION A healthy 3-year-old male presented with worsening vertigo, headaches, and emesis. Radiographic studies demonstrated a midline posterior fossa mass in the fourth ventricle. Following a gross total resection, pathology demonstrated a posterior fossa ependymoma, group A. Next generation sequencing (NGS) using our institution’s clinically validated panel, “CinCSeq”, demonstrated a POT1 splice site variant (c.1164-1G &amp;gt;A; variant allele frequency 46%). Paired germline testing via the molecular characterization initiative confirmed this variant as a heterozygote in the patient. Genetic testing confirmed a germline mutation in his mother who has a history of multiple nevi. He completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date. DISCUSSION To our knowledge, this represents the first documented pediatric ependymoma with a familial, germline POT1 mutation. Somatic POT1 mutational frequency as determined by NGS in 60,000 solid tumors occurs at a rate of 2.94%. 45/60,000 were ependymomas with 1 non-benign POT1 mutation. Alterations of telomere maintenance have been reported in infratentorial ependymomas through increased human telomerase reverse transcriptase (hTERT) expression. This case sheds light on potential new mechanisms/predispositions for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 mutation may have been discovered incidentally in this case. Further research into an association between POT1 and ependymomas is needed to advance our understanding.
RBIO-11. BASAL BCL-2-INTERACTING MEDIATOR OF CELL DEATH (BIM) RESPONSIVENESS CORRELATES WITH RADIOSENSITIVITY IN MENINGIOMA
Authors: Maya Harary, Elizabeth Fernandez, Joshua Casaos, Jeremie Vitte, David Nathanson, Brian Na, Robert Prins, Marco Giovannini, Richard Everson
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Radiotherapy remains the primary adjunctive treatment for recurrent or progressive meningioma. Nevertheless, varied clinical response to radiotherapy in meningioma remains a challenge, particularly in higher grade tumors. Currently there is a paucity of predictors of radio-sensitivity. Bim peptide is an intrinsic mediator of apoptosis, and Bim-responsiveness has been postulated as a metric of general sensitivity to apoptotic stress. Herein we investigated its utility as a metric of radio-sensitivity in meningioma. METHODS In an in vitro model of meningioma, a number of immortalized human and murine meningioma cell lines and patient-derived primary cultures (WHO grades 1 + 2), were exposed to ionizing radiation at range of doses (0, 2, 4, 8, 16Gy); cells were counted (Celigo, Nexelcom) to assess for growth. Separately, cultures were irradiated at 4Gy and apoptosis was analyzed 24H later using Annexin/PI staining by flow cytometry (Attune NxT). Lastly, untreated cultures were exposed to Bim peptide as a range of doses (0.01uM-10uM); induction of apoptosis was assessed via cytochrome C staining by flow cytometry. RESULTS We were able to recapitulate a wide range of radio-sensitivities both by growth metrics and radiation-induced apoptosis. Immortalized lines showed more radiation-induced growth inhibition relative to primary cultures (p = 0.03). Activation of apoptosis in response to Bim exposure demonstrated a similarly wide range of basal apoptotic sensitivities, akin to that seen for radio-sensitivity. In fact, there was a significant correlation (Pearson, p &amp;lt; 0.01) between Bim-responsiveness and levels of radiation-induced apoptosis. CONCLUSIONS We identify basal state Bim-responsiveness as a potential predictor of radio-sensitivity in meningioma. Further work in this vein may shed light on mechanisms of radio-resistance in meningioma, particularly with respect to the interaction of Bim with the anti-apoptotic members of the Bcl-2 family.
CTIM-41. ONCOLYTIC IMMUNOTHERAPY LINKS IMMUNOACTIVATION TO SUBJECT SURVIVAL IN PHASE I TRIAL OF RECURRENT GLIOBLASTOMA
Authors: Alexander Ling, Isaac Solomon, Hiroshi Nakashima, Andres Santos, Francesca Barone, David Reardon, E Antonio Chiocca
Journal: Neuro-Oncology (2023)

Abstract A “first-in-human” phase 1 trial of intralesional injection of CAN-3110, an immunotherapeutic oncolytic based on herpes simplex virus 1 (HSV1), was conducted in 41 subjects with recurrent high-grade glioma (rHGG). The impact of CAN-3110 on the tumor immune microenvironment was assessed using immunohistochemistry, multiplexed immunofluorescence, TCR-beta DNA sequencing, and bulk RNA sequencing of paired pre- and post-treatment samples. These analyses were combined with patient features to identify potential biomarkers of therapy response in rHGG. In IDH wild type recurrent glioblastoma (IDHwt rGBM) patients, post-treatment survival times were positively associated with positive pre-treatment HSV1 serology after controlling for additional covariates such as tumor volume, age, gender, CAN-3110 dose, etc. (HR = 0.16, p &amp;lt; 0.001, n = 32, CoxPH). Positive HSV1 serology was also significantly associated with clearance of CAN-3110 from injected tumors. Interestingly, increased intratumoral CD8 and CD4 T cell numbers following treatment were positively associated with prolonged survival in HSV1 seropositive patients (p = 0.017 and 0.026, respectively), but not when analyses were conducted including HSV1 seronegative patients. Likewise, post-treatment immune expression signatures (such as for antitumor cytokines, T cell traffic, etc.) were more strongly associated with prolonged survival for HSV1 seropositive patients than for seronegative patients, and most assessed immune signatures only became associated with survival after CAN-3110 treatment. Extended survival was also associated with increased TCR-beta diversity following therapy in both the tumor and in PBMCs. Combined with a lack of observed dose-limiting toxicities and a median post-treatment survival of 14.2 months (95% CI: 9.5-15.7) in IDHwt rGBM patients with positive HSV1 serology, these data provide evidence that intralesional CAN-3110 treatment can instigate immune activation in a traditionally immunologically cold tumor and that this immune activation may influence survival time—particularly when patients have had prior exposure to HSV1. (clinicaltrials.gov NCT03152318).
PATH-14. MSI GENETIC FINDINGS IN FAMILIAL TURCOT SYNDROME 1 ASSOCIATED TO REPRODUCTION FAILURE
Authors: Nouha Bouayed Abdelmoula, Balkiss Abdelmoula
Journal: Neuro-Oncology (2023)

Abstract The aim of this study was to report MSI genetic findings in a three-generation Tunisian pedigree of Turcot syndrome 1 (TS1), characterized by an uncommon association with infertility and child mortality. Microsatellite instability testing and genetic counseling were offered to affected members and their young relatives, to provide optimal clinical and preventive care. The index case of our Tunisian pedigree was a 38-year-old female, in whom histologic assessment of endoscopic specimens through a colorectal adenoma resection during screening colonoscopy, showed a tubular adenoma of the lower rectum with low-grade intraepithelial neoplasia. The screening procedure was conducted because her two brothers, 58 and 60 years old, harbored respectively glioblastoma multiforme and colon adenocarcinoma. The first brother exhibited an intracranial hypertension syndrome and a left hemiplegia leading to the diagnosis of a brain tumor. Whereas the second brother manifested diarrhea and intestinal colic that were investigated by colonoscopy. Histologic assessment of endoscopic specimens through a right preangular budding formation showed a well-differentiated liberkhunian adenocarcinoma that was treated by a right hemicolectomy. Genetic assessment at the germinal and somatic levels was conducted for the three affected patients using conventional microsatellite instability (MSI) testing methods. Molecular analysis determined MSI status of the tumors and classified them into stable types (MSS) without any mutation or aberrant expression of MLH1, MSH2, MSH6, and PMS2 genes. Familial history revealed, at the first generation, a consanguineous couple who lost several children at a young age. This couple gave birth to eight children, three of whom were infertile, three affected by MMS TS1 and two healthy. The third generation consists of 15 children, so far, without any tumors. Genetic counselling for TS remains difficult because of the rarity of the condition, its shifting definition over the years, and its genetic and phenotypic heterogeneity.
EXTH-47. TUMOUR-TARGETED PAN-RAS INHIBITION AS A NOVEL THERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Stefanie-Grace Sbergio, Peter Liang, Greg Beilhartz, Palak Patel, Arun Anguraj Vadivel, Roman Melnyk, Cynthia Hawkins
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Diffuse Intrinsic Pontine Glioma (DIPG) has a median survival of 9 months following diagnosis in children 7-9 years old. Current therapeutic options are limited to radiation and thus tumour specific vulnerabilities are the subject of ongoing research. One such vulnerability is RAS signalling due to its upregulation in DIPG. RAS regulates cellular proliferation and survival making it an attractive target. Based on diphtheria toxin (DT), we have developed a molecular chimera which selectively binds a DIPG cell surface receptor and releases a RAS cleaving peptidase (RRSP). We hypothesize that using a DIPG targeted RRSP conjugated chimera will reduce tumour viability and improve survival in DIPG models. METHODS Viability of SU-DIPG XIII, XVII, XXV, 36 and 50 cell lines treated with RRSP-DTB, and a DIPG targeted RRSP conjugated chimera was measured using CellTiterGlo Luminescent Assay. Proteomic analysis and single-cell RNA sequencing was used to identify a cell surface receptor upregulated on tumour cell populations from patient samples. SU-DIPG 36 orthotopic xenograft mice were treated with our DIPG targeted RRSP conjugated chimera or vehicle for one week delivered into the pons via osmotic pump and monitored using bioluminescent imaging. RESULTS RRSP-DTB successfully reduces DIPG cell viability in vitro with an EC50 between 0-3 picomolar, demonstrating successful toxicity mediated by RRSP. This is supported by ablation of RAS verified on Western Blot. ANTXR1 receptor was identified as upregulated in tumour cell populations, and a TEM8 conjugated RRSP chimera was developed. RRSP-TEM8 has an EC50 of 5-70 picomolar in vitro and significantly improves survival in vivo with a median survival of 68 days (n = 14) compared to the vehicle control (n = 14) 57 days (p = 0.02). Our results present a successful novel therapeutic as our RRSP chimera, RRSP-TEM8, effectively targets DIPG cells and reduces cell viability to improve survival.
NIMG-72. CONTRALATERAL PREDOMINANT BLOOD SUPPLY OF FALX AND PARASAGITTAL MENINGIOMA BASED ON ANGIOGRAPHIC ANALYSIS
Authors: Sho Tamai, Shingo Tanaka, Tomoya Kamide, Kouichi Misaki, Mitsutoshi Nakada
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Preoperative prediction of blood supply in meningiomas is important to avoid unexpected intraoperative bleeding. Herein, we investigated the relationship between the location of meningioma and the dominant side of feeding arteries. METHOD: Between January 2018 and December 2020, a total of 101 consecutive patients underwent craniotomy for meningioma at our hospital. Among them, 43 cases in which the lesions were clearly localized on the right or left sides received preoperative angiography including bilateral common or external carotid artery (ECA) imaging. A region of interest (ROI) was set at the most stained area in (X) meningioma and (Y) main trunk of the ECA. In each affected side (AS) and healthy side (HS), the ratio of ROI (X) value to ROI (Y) value; tumor / vessel ratio (TVR = 0 ~ 1) was calculated. Multivariate analysis was performed to compare TVR between AS and HS, and to analyze factors associated with TVR, such as site of origin (convexity, skull base and relating falx), age, gender, WHO grading, and tumor diameter. RESULTS TVR was significantly higher in AS (0.60; 0.41 - 0.91) than HS (0.47; 0.39 - 0.99) (p=0.0003). HS was superior to AS in 10 cases, all of which were falx (6 of 9 cases) or parasagittal (4 of 10 cases) meningioma. 53% of falx and parasagittal meningiomas showed HS predominant TVR. Concerning factors associated with the TVR of HS predominance, falx origin was extracted as an independent factor (p&amp;lt; 0.0001). DISCUSSION The vessels crossing in the falx, which consist with particular anatomical structure, fusing the meningeal layers in each side of dura mater would contribute to this finding. CONCLUSION Falx and parasagittal meningiomas should consider the predominant influx of tumor feeding vessels from HS.
CTIM-39. A PHASE 1B STUDY OF PEMBROLIZUMAB, IBRUTINIB AND RITUXIMAB IN RECURRENT/REFRACTORY (RR) PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: Ugonma Chukwueke, Isobel Wright, Alona Muzikansky, Alyssa Russ, Brittney Fontana, Vanessa Kats, Colin O'Donnell, Renee Scalfani, Brenda Acevedo-Naranjo, Eudocia Lee, Luis Nicolas Gonzalez Castro, Jose Ricardo McFaline-Figueroa, Elisa Aquilanti, Gilbert Youssef, Rameen Beroukhim, Deborah Forst, David Reardon, Patrick Wen, Tracy Batchelor, Alexandra Torres, Jennifer Stefanik, Jennifer Fisher, David Meredith, Mark Murakami, Yuri Garcia, Margaret Shipp, Lakshmi Nayak
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND PCNSL exhibit B-cell receptor (BCR) pathway activation due to CD79B and MYD88 mutations, concurrently with 9p24.1/PD-L1/PD-L2 copy number alterations. These genetic features suggest complementary approaches of targeting PD1, BCR/BTK (Bruton’s tyrosine kinase) and CD20. Pembrolizumab, ibrutinib and rituximab have each been used as monotherapy in RR PCNSL. We investigate these agents in combination to determine tolerability and synergistic efficacy. METHODS This is a phase 1b/2 study of pembrolizumab, ibrutinib and rituximab in RR PCNSL patients. In phase 1b, patients were accrued using a 3 + 3 design to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). Patients were treated with pembrolizumab 200mg IV every 3 weeks, ibrutinib oral daily and rituximab 375mg/m2 IV weekly (for 4 doses). Two dose levels (DL) of ibrutinib (DL1: 560 mg, DL2: 840 mg) were evaluated. Primary endpoint is progression-free survival at six months (PFS6); secondary endpoints include safety, tolerability, objective response rate (ORR), duration of response (DOR), progression-free and overall survival. RESULTS We completed accrual on the phase 1b part and report results of 10 evaluable patients (50% women). The median age was 74 years (38-82) and median ECOG 1 (0-1). There was 1 DLT at DL1 (grade 4 transaminases) and 2 DLTs at DL2 (hypertension, flu-like symptoms); the MTD/R2PD of ibrutinib with pembrolizumab and rituximab is 560mg. The most common grade 3/4 adverse events were elevated transaminases and decrease in lymphocyte counts. There were 13 dermatologic events, all &amp;lt; grade 3. Reasons for discontinuing treatment include progression (6), consent withdrawal (1), toxicity (2). The ORR is 80% (6 complete responses, 2 partial responses). As of June 2023, the median DOR is 177 days (49-619); PFS6 is 50%. CONCLUSIONS The combination of pembrolizumab, ibrutinib and rituximab is well-tolerated with manageable side effects and encouraging efficacy. The phase 2 portion of the study is open.
CTIM-18. NRG ONCOLOGY STUDY BN007: RANDOMIZED PHASE II/III TRIAL OF IPILIMIUMAB (IPI) PLUS NIVOLUMAB (NIVO) VS. TEMOZOLOMIDE (TMZ) IN MGMT-UNMETHYLATED (UMGMT) NEWLY DIAGNOSED GLIOBLASTOMA (NGBM)
Authors: Andrew Lassman, Mei-Yin Polly, Fabio Iwamoto, Andrew Sloan, Tony Wang, Kenneth Aldape, Jeffrey Wefel, Vinai Gondi, Alonson Gutierrez, Mohammed Manasawala, Mark Gilbert, Erik Sulman, Jedd Wolchok, Richard Green, Elizabeth Neil, Rimas Lukas, Samuel Goldlust, Matija Snuderl, James Dignam, Minhee Won, Benjamin Movsas, Minesh Mehta
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND New therapies are especially needed for uMGMT nGBM. NRG Oncology BN002 (phase I) demonstrated safety and preliminary efficacy of Ipi+Nivo for nGBM, leading to BN007 as phase II/III. METHODS Adults with uMGMT nGBM (WHO 2016) and KPS ≥ 70 were randomized to RT and concurrent and adjuvant Ipi+Nivo or TMZ, stratified by glioma-recursive partitioning analysis class (RPA), intent to use tumor-treating fields (NCT04396860). Phase II primary endpoint was progression-free survival (PFS), powered 95% to detect a hazard ratio (HR) ≤0.58 with 1-sided 0.15 significance after 100 events. If p &amp;lt; 0.15, then phase III would accrue with overall survival (OS) as primary endpoint. Corticosteroids were disallowed at Ipi+Nivo start. Histology, biomarkers, and PFS were assessed centrally. RESULTS Among 374 patients screened, 159 were randomized in phase II (79 Ipi+Nivo, 80 TMZ). Demographics (age median 60 years, range 28-79; male 66%, white 88%, not Hispanic/Latino 89%), KPS (90-100 61%), extent of resection (gross total 65% per local PI), and RPA (III 10%, IV 73%, V 17%) were well-balanced between arms. After 100 PFS events, the pre-planned phase II analysis demonstrated no improvement for Ipi+Nivo vs. TMZ [median 7.7 (95% CI: 6.5, 8.5) vs. 8.5 (95% CI: 7.1, 10.4) months; HR 1.47 (95% CI: 0.98-2.2); 1-sided p = 0.96]. OS is immature ( &amp;gt;50% alive, 13.7 months median follow-up) but without observed difference between arms [median ~13 months each; HR 0.95 (95% CI: 0.61-1.49); 1-sided p = 0.36]. On the Ipi+Nivo arm, treatment-related grade 3, 4, and 5 events were reported in 26 (33.3%), 4 (5.1%), and 2 (2.6%; colitis and autoimmune disorder, n = 1 each) patients. CONCLUSIONS Ipi+Nivo did not improve PFS for uMGMT nGBM. Accrual permanently closed after phase II. No new safety signals were identified. Molecular analyses and survival follow-up are ongoing. FUNDING: NCI Grants U10CA180868, U10CA180822, U24CA196067 (NRG Oncology Operations, SDMC, Specimen Bank).
CTIM-19. ONCOLYTIC DNX-2401 VIROTHERAPY PLUS PEMBROLIZUMAB IN RECURRENT GLIOBLASTOMA: A PHASE 1/2 TRIAL
Authors: Farshad Nassiri, Vikas Patil, Leeor Yefet, Olivia Singh, Jeff Liu, Rachel Dang, Takafumi Yamaguchi, Mariza Daras, Timothy Cloughesy, Howard Colman, Priya Kumthekar, Clark Chen, Robert Aiken, Morris Groves, Shirley Ong, Rohan Ramakrishna, Michael A Vogelbaum, Simon Khagi, Thomas Kaley, Jason Melear, David Peereboom, Analiz Rodriguez, Maxim Yankelevich, Suresh Nair, Vinay Puduvalli, Kenneth Aldape, Andrew Gao, Alvaro Lopez-Janeiro, Carlos de Andrea, Marta Alonso, Paul Boutros, Joan Robbins, Warren Mason, Adam Sonaben, Roger Stupp, Juan Fueyo-Margareto, Candelaria Gomez-Manzano, Frederick Lang, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5months (10.7–13.5months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
PATH-15. GLIOBLASTOMA, IDH-WILDTYPE WITHOUT KEY MOLECULAR FEATURES.
Authors: Ryuta Saito, Kazuya Motomura, Fumiharu Ohka, Junya Yamaguchi, Sachi Maeda, Tomohide Nishikawa, Kosuke Mizutani, Yuji Kibe, Hiroki Shimizu, Yuhei Takido
Journal: Neuro-Oncology (2023)

Abstract Molecular alterations that predict aggressive behavior of astrocytic tumors include EGFR amplification, TERT promoter (pTERT) mutations, gain of chromosome 7 and loss of chromosome 10. During January 2020 and February 2023, we encountered 21 cases of pathologically diagnosed glioblastoma, IDH-wildtype without the above-mentioned molecular characteristics. In this study, we tried to characterize these tumors. For all cases, genomic DNA was extracted from fresh frozen tissue. Using extracted DNA, to analyze the status of IDH mutation, 1p/19q codeletion, pTERT mutation, EGFR gene amplification, combined gain of entire chromosome 7, and loss of entire chromosome 10 (+7/− 10), whole exome sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) was performed. In addition, gene panel testing was performed for suspected familial cases. Among 21 cases, 2 harbored histone G34 mutation and was diagnosed as diffuse hemispheric gliomas, H3 G34-mutant. Among the rest 19 patients, CDKN2A/B homozygous deletions were detected in 7. Three of the rest 12 patients were diagnosed as patients with Li Fraumeni syndrome. Glioblastoma IDH-wildtype CNS WHO grade 4 typically presents necrosis and/or microvascular proliferation. Molecular alterations including EGFR amplification, pTERT mutations, gain of chromosome 7 and loss of chromosome 10 are key features that characterize GBM IDH-wildtype. However, some of the pathologically diagnosed GBM, do not carry these gene alterations. Among those, there existed cases harboring CDKN2A/B homozygous deletions or H3 G34 mutations, and cases suffering Li Fraumeni syndrome.